This competitive renewal application of P01 CA100730 seeks funds to continue the study of highly integrated retrovirus models to elucidate essential cellular mechanisms that define lymphocyte transformation and disease. The study of retroviruses has provided fundamental and critical knowledge for defining the mechanisms of cell transformation as well as fundamental paradigms of cell biology. The interactive nature, established record of collaborations, and focus of the individual projects and cores that constitute the proposed PPG continuation are directly supportive of NCI's strategic plans and goals. Our goals were realized with robust productivity over the last four years demonstrated by 64 peer-reviewed manuscripts 70% interactive between PPG investigators. The continuation of the Program will extend upon the established interactions through inter-related goals to define critical events that control the transition of lymphocytes from activation through immortalization and transformation. Project 1 uses retroviruses to provide novel insights into how they alter transcription and DNA damage/repair signaling to establish persistent infections and set the stage for cellular transformation. Project 2 (Dr. Green) will define novel post-transcriptional mechanisms of retroviruses and working together with Dr. Lairmore (Project 1), will comparatively test each protein in viral replication and lymphocyte transformation. Project 3 working collaboratively with multiple PPG investigators will examine the fundamental translational control mechanisms in both retroviruses and in crucial growth control genes. Project 4 (Drs. Weilbaecher, Washington University and Rosol, Ohio State University) combine their expertise with PPG investigators to study the role of bone microenvironment in osteolytic and osteoblastic tumor models. Project 5 (Dr. Ratner) continues the highly dynamic collaborations between each University to test the contribution of the inflammatory microenvironment in carcinogenesis using unique transgenic mouse models. The PPG consists of five interactive Projects and three highly supportive Cores. Each project is related to two central components involving the regulation of lymphocyte signaling and gene expression by retroviruses or alterations of the cellular microenvironment leading to transformation and paraneoplastic disease. The interactive nature of the PPG will provide rationale hypotheses to support translational studies to define therapeutic intervention against retrovirus-induced lymphoma and refine animal models to determine molecular determinants of retrovirus-induced cancer.